Reactive antibacterial compound and preparation method thereof

ABSTRACT

A reactive antibacterial compound is represented by formula (I) or (II): 
                         
wherein R 1  represents OCN-L-NHCOOR′, OCN-L-NHCONHR′, OCN-L-NHCOSR′, OCN-L-COOR′, or OCN-L-COONHR′. G1 represents OCN-M-NHCOOG′, OCN-M-NHCONHG′, OCN-M-NHCOSG′, OCN-M-COOG′, or OCN-M-COONHG′. L, M, R′ and G′ independently for each occurrence represent divalent alkyl and cycloalkyl having from 1 to 18 carbon atoms, optionally substituted by up to 18 heteroatoms. R 4  and G 4  independently for each occurrence represent a divalent alkyl and cycloalkyl having from 1 to 18 carbon atoms, optionally substituted by up to 18 heteroatoms. G 2  and G 3  independently for each occurrence represent —H, —F, —Cl, —Br, —I, —OCH3, —OCH2CH3, —OPr, —CN, —SCN, —NO, —NO2, a monovalent unsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to 7 carbon atoms. Z and X independently for each occurrence represent —COO, —SO3, or —OPO2OR 5 . R 5  represents a monovalent unsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to 6 carbon atoms.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. national stage of InternationalApplication No. PCT/CN2015/090059, filed on Sep. 18, 2015, which claimspriority of International Application No. PCT/CN2015/072439 filed onFeb. 6, 2015. Each of the above applications are incorporated herein byreference in their entireties.

TECHNICAL FIELD

The present application generally relates to the field of antibacterialtechnologies, particularly to a reactive antibacterial compound and apreparation method thereof, and more particularly to a reactiveantibacterial compound with positively charged nitrogen atoms and apreparation method thereof.

BACKGROUND

Bacterial and fungal infections have become a worldwide problem thatthreatens human health and is highly concerned in the global health careindustry. One of the important means to solve the problem of bacterialor fungal infections is to impart antibacterial properties to thesurface of a material or a product, so as to prevent bacteria or fungifrom growing or proliferating on the surface of the material or theproduct, or even to kill the bacteria or fungi already present on thesurface. The usual solution is to adhere or anchor antibacterialcomponents or materials to the surface of the product by means of spraycoating and/or chemical bonding, thereby achieving the antibacterialproperties. Known antibacterial materials are widely applied onceramics, glass products, plastics, rubbers, fibers, papers, painting,etc., such as household appliances, furniture, janitorial supplies, foodpackages, and clothing. At present, world-wide antibacterial materialsmay be classified into four categories: (1) inorganic antibacterialagents, such as nano-titanium dioxide, nano-silver, nano-copper, andions thereof; (2) organic antibacterial agents, such as quaternaryammonium salts, alcohols, haloamines, biguanides, and thiazoles; (3)polymeric antibacterial agents, such as polymeric quaternary ammoniumsalts; and (4) natural and modified antibacterial agents, such aschitosans and sorbic acids.

In order to impart antibacterial properties to the surface of thematerial or product, the most common method is to cover the surface witha coating containing antibacterial agents (such as nano-silver,nano-copper, and ions thereof, or other antibacterial agents), and/ornano-silver, nano-copper, silver ions, copper ions, other heavy metals.Relying on the slow release of metal ions into the ambientenvironmental, the purpose of bacteriostasis or sterilization is therebyachieved. However, the antibacterial capability of these metal ionsgradually reduces over time until the antibacterial capability iscompletely lost, meanwhile, microorganisms may be induced to mutate bythe metal ions, thus increasing the probability that the microorganismsdevelop drug resistance. In addition, harmfulness of nano-materials hasgradually been recognized and paid attention by human beings.

The organic antibacterial compounds, such as quaternary ammonium salts,alcohols, haloamines, biguanides, and thiazoles, bear thecharacteristics of taking effect in short time, and extinguishingbacterias efficiently. This category of antibacterial agents mainlyincludes quaternary ammonium salts and quaternary phosphonium salts.Generally, cell walls of bacteria are negatively charged, and ions, suchas quaternary ammonium salts and the quaternary phosphonium salts, arepositively charged. The quaternary ammonium salts with positive chargesare liable to be absorbed by the bacteria, penetrating the cell wallsafter approaching the bacteria, being bonded to the cytomembrane, anddisrupting the composition of the cytomembrane, which results in leakingof intracellular materials and eventually death of the bacteria.However, the chemical activeness of the quaternary ammonium salts, whichexist substantially in a free state during use and have high toxicityand strong irritation, is low. When used as antibacterial agents, thequaternary ammonium salts have poor heat resistance, tend to migrate andcan be washed easily. Moreover, the quaternary ammonium salts tend toenrich on skins of human bodies gradually, thus a long-term use ofquaternary ammonium salts may cause microorganisms to mutate, resultingin drug resistance for these microorganisms. Meanwhile, the organicantibacterial agents have poor heat resistance, thereby limiting theiruse range thereof.

The polymeric quaternary ammonium salt antibacterial agents can overcomeproblems of micro-molecule antibacterial agents, such as being volatile,unworkable, chemically unstable. Moreover, the polymeric quaternaryammonium salt antibacterial agents exhibit good antibacterialactiveness, and are less permeating, which helps drawing attention ofthe people. At present, however, the unimmobilized polymericantibacterial agents also exhibit drawbacks such as high leachabilityand lack of sustainability, which presents pressure to the ambientenvironment as well.

The natural antibacterial agents are derived from extracts of naturalplants, animals or minerals, whose main antibacterial mechanism issimilar to that of the organic quaternary ammonium salts, but are lesseffective than the organic antibacterial agents, and products of thenatural antibacterial agents are not yet mature. Another drawback of thenatural antibacterial agents is that they are not suitable for massproduction, so that their application thereof is limited.

Therefore, there is a need to develop and prepare antibacterial agentswhich are green, immobilizable, and durable.

SUMMARY

According to some embodiments of the present disclosure, a reactiveantibacterial compound is provided, which exhibits excellentantibacterial property and behaves as hydrophilic, and can react withand bind to functional groups on surfaces of natural fibers, syntheticfibers and polymeric materials by a terminal isocyanate, therebyachieving durable antibacterial effects. The terminal isocyanate mayrefer to an isocyanate at the end of a molecular chain.

In some embodiments, the antibacterial compound is a zwitterioniccompound having a terminal isocyanate and a quaternary ammonium group.The positive charge of a quaternary nitrogen atom may damagecytomembrane of microorganisms, thereby denaturing protein and damagingcell structures. The microorganisms may include but not limited to E.coli, S. typhimurium, P. aeruginosa, S. aureas, C. albicans, sulfatereducing bacteria, Gram-positive bacteria, Gram-negative bacteria, S.epidermidis, E. faecalis, C. xerosis, B. anthracis, etc. Theantibacterial compound may be used as a sterilizing agent or abacteriostatic agent to prevent infections, terminate microorganisms orinhibit physiological functions of the microorganisms, and thus treatingeffectively the infections caused by these microorganisms, or confiningpollution caused by the same.

In some embodiments, the antibacterial compound may be chemically boundto the surface of materials through a terminal isocyanate. Theantibacterial compound may be applied to textile, medicine, food, andagriculture fields, but not limited thereto. For example, the isocyanatemay be bound to a hydroxyl or amino on surface of a fiber, a cottontextile, or a nylon, to produce an antibacterial textile with detergentresistance; may be bound to a hydroxyl or amino on surface of a medicalperfusion tube or packaging material, to produce an antibacterialmedical product; or may be bound to a hydroxyl or amino on the surfaceof a food package or food preservation material, to produce anantibacterial packaging material.

According to an aspect of the present disclosure, the antibacterialcompound may be represented by the general formula (I):

wherein, R₁ represents OCN-L-NHCOOR′, OCN-L-NHCONHR′, OCN-L-NHCOSR′,OCN-L-COOR′, or OCN-L-COONHR′;

L represents a divalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 18 carbon atoms, optionally substituted by atmost 18 heteroatoms;

R′ represents a divalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 18 carbon atoms, optionally substituted by atmost 18 heteroatoms;

R₂ and R₃ independently for each occurrence represent a monovalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to18 carbon atoms, optionally substituted by at most 18 heteroatoms;

R₄ independently represents a divalent unsubstituted or substitutedalkyl, cycloalkyl, or aryl having from 1 to 18 carbon atoms, optionallysubstituted by at most 18 heteroatoms;

Z represents —COO, —SO₃, or —OPO₂OR₅; and

wherein, R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms.

In some embodiments, in the antibacterial compound, the R₂ and R₃ arethe same or different groups.

In some embodiments, in the antibacterial compound, the R₂ and the R₃independently for each occurrence represent —(CH₂)_(u)CH₃, and u is aninteger within a range from 0 to 17. Preferably, u is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; further more preferably,u is 0, 1, 2, 3, or 4; more preferably, u is 0, 1, or 2.

In some embodiments, in the antibacterial compound, the Z represents—SO₃.

In some embodiments, in the antibacterial compound, the Z represents—CO₂.

In some embodiments, in the antibacterial compound, the Z represents—OPO₂OR₅.

In some embodiments, in the antibacterial compound, the R₅ represents—(CH₂)wCH₃, and w is an integer within a range from 0 to 5.

In some embodiments, in the antibacterial compound, the R₄ and the R′independently for each occurrence represent —(CH₂)_(n)—, and n is aninteger within a range from 1 to 18. Preferably, n is 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; more preferably, n is 1,2, 3, 4, 5, 6, 7, 8, 9, or 10; further more preferably, n is 0, 1, 2, 3,4, 5, 6, or 7.

In some embodiments, in the antibacterial compound, the R₁ representsOCN-L-NHCOOR′ or OCN-L-NHCONHR′.

In some embodiments, in the antibacterial compound, the L represents:

According to another aspect of the present disclosure, the antibacterialcompound are represented by the general formula (II):

wherein, G₁ represents OCN-M-NHCOOG′, OCN-M-NHCONHG′, OCN-M-NHCOSG′,OCN-M-COOG′, or OCN-M-COONHG′;

M represents a divalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 18 carbon atoms;

G′ represents a divalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 18 carbon atoms;

G₂ and G₃ independently for each occurrence represent —H, —F, —Cl, —Br,—I, —OCH₃, —OCH₂CH₃, —OPr, —CN, —SCN, —NO, —NO₂, a monovalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to7 carbon atoms;

G₄ represents a divalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 18 carbon atoms;

X represents —COO, —SO₃, or —OPO₂OR₅; and

R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms.

In some embodiments, in the antibacterial compound, the G₁ representsOCN-M-NHCOOG′ or OCN-M-NHCONHG′.

In some embodiments, in the antibacterial compound, the G₂ and G₃ arethe same or different groups.

In some embodiments, in the antibacterial compound, the G₂ and G₃independently for each occurrence represent —H, —CH₃, —CH₂CH₃, —NO₂, —F,—Cl, —Br, or —I.

In some embodiments, in the antibacterial compound, the X represents—SO₃.

In some embodiments, in the antibacterial compound, the X represents—CO₂.

In some embodiments, in the antibacterial compound, the X represents—OPO₂OR₅.

In some embodiments, in the antibacterial compound, the R₅ represents—(CH₂)_(w)CH₃, and w is an integer within a range from 0 to 5.Preferably, w is 0, 1, 2, 3, or 4, more preferably, w is 0, 1, or 2.

In some embodiments, in the antibacterial compound, the G₄ and the G′independently for each occurrence represent —(CH₂)_(n)—, and n is aninteger within a range from 1 to 18. Preferably, n is 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; more preferably, n is 1,2, 3, 4, 5, 6, 7, 8, 9, or 10; further more preferably, n is 0, 1, 2, 3,4, 5, 6, or 7.

In some embodiments, in the antibacterial compound, the M represents:

According to another aspect of the present disclosure, a preparationmethod for an antibacterial compound include:

reacting tertiary amine represented by the general formula (III) with areactant B represented by the general formula (IV), and generating amixture;

wherein: the Y represents —OH, —NH₂, or —SH; R′ represents a divalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to18 carbon atoms; R₂ and R₃ independently for each occurrence represent amonovalent unsubstituted or substituted alkyl, cycloalkyl, or arylhaving from 1 to 18 carbon atoms; L represents a divalent unsubstitutedor substituted alkyl, cycloalkyl, or aryl having from 1 to 18 carbonatoms; and D represents —COOH or —NCO;

reacting the mixture with a reactant A, and generating the antibacterialcompound;

wherein: the reactant A represents propane sultone, butane sultone,β-propiolactone, X(CH₂)_(v)CO₂—Mt⁺, X(CH₂)_(v)SO₃—Mt⁺, or cyclicphosphate ester, the X represents Br, Cl, or I, v is an integer greaterthan 0, Mt⁺ represents Li⁺, Na⁺, K⁺, NH₄ ⁺, Ag⁺, ½Mg²⁺, or ½Ca²⁺, andthe cyclic phosphate ester represents:

wherein: R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms; and R₆ represents adivalent unsubstituted or substituted alkyl having from 1 to 6 carbonatoms.

In some embodiments, in the preparation method for the antibacterialcompound, the tertiary amine and the reactant B are reacting in thepresence of catalyst C, and the catalyst C represents at least one oforganic amine, a phosphorus compound, or a metal-containing catalyst.

In some embodiments, in the preparation method for the antibacterialcompound, the catalyst C represents the metal-containing catalyst.

In some embodiments, in the preparation method for the antibacterialcompound, the metal-containing catalyst represents tin tetrachloride,tetrabutyl tin, tributyl tin chloride, dibutyl tin dichloride, butyl tintrichloride, tributyl tin cyanide, dibutyl tin diacetate, dibutyl tindioctoate, tributyl tin octoate, diphenyl tin dioctoate, dibutyl tindibutoxy, dibutyl tin bis(acetylacetoate), dibutyl tinbis(isooctylmaleate), dioctoate tin oxide, dibutyl tin sulfide, stannousoleate, stannous tartrate, dibutyl tin dilaurate, stannous octoate, ormetal naphthenate.

In some embodiments, in the preparation method for the antibacterialcompound, the catalyst C represents the metal naphthenate.

In some embodiments, in the preparation method for the antibacterialcompound, the metal naphthenate represents at least one of coppernaphthenate, zinc naphthenate, lead naphthenate, lithium naphthenate,cobalt naphthenate, nickel naphthenate, cadmium naphthenate, mercurynaphthenate, indium naphthenate, or bismuth naphthenate.

According to another aspect of the present disclosure, a preparationmethod for an antibacterial compound include:

1) reacting pyridine represented by the general formula (V) with areactant B represented by the general formula (IV), and generating amixture;

wherein: the Q represents —OH, —NH₂, or —SH; G′ represents a divalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to18 carbon atoms; G₂ and G₃ independently for each occurrence represent—H, —F, —Cl, —Br, —I, —OCH₃, —OCH₂CH₃, —OPr, —CN, —SCN, —NO, —NO₂, amonovalent unsubstituted or substituted alkyl, cycloalkyl, or arylhaving from 1 to 7 carbon atoms; D represents —COOH or —NCO; and Lrepresents a divalent unsubstituted or substituted alkyl, cycloalkyl, oraryl having from 1 to 18 carbon atoms.

2) reacting the mixture with a reactant A, and generating theantibacterial compound;

wherein: the reactant A represents propane sultone, butane sultone,β-propiolactone, X(CH₂)_(v)CO₂—Mt⁺, X(CH₂)vSO₃—Mt⁺, or cyclic phosphateester, the X represents Br, Cl, or I, v is an integer greater than 0,Mt⁺ represents Li⁺, Na⁺, K⁺, NH₄ ⁺, Ag⁺, ½Mg²⁺, or ½Ca²⁺, and the cyclicphosphate ester represents:

wherein: R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms; and R₆ represents adivalent unsubstituted or substituted alkyl having from 1 to 6 carbonatoms.

In some embodiments, in the preparation method for the antibacterialcompound, the pyridine and the reactant B are reacting in the presenceof catalyst C, and the catalyst C represents at least one of organicamine, a phosphorus compound, or a metal-containing catalyst.

In some embodiments, in the preparation method for the antibacterialcompound, the catalyst C represents the metal-containing catalyst.

In some embodiments, in the preparation method for the antibacterialcompound, the metal-containing catalyst represents tin tetrachloride,tetrabutyl tin, tributyl tin chloride, dibutyl tin dichloride, butyl tintrichloride, tributyl tin cyanide, dibutyl tin diacetate, dibutyl tindioctoate, tributyl tin octoate, diphenyl tin dioctoate, dibutyl tindibutoxy, dibutyl tin bis(acetylacetoate), dibutyl tinbis(isooctylmaleate), dioctoate tin oxide, dibutyl tin sulfide, stannousoleate, stannous tartrate, dibutyl tin dilaurate, stannous octoate, ormetal naphthenate.

In some embodiments, in the preparation method for the antibacterialcompound, the catalyst C represents the metal naphthenate.

In some embodiments, in the preparation method for the antibacterialcompound, the metal naphthenate represents at least one of coppernaphthenate, zinc naphthenate, lead naphthenate, lithium naphthenate,cobalt naphthenate, nickel naphthenate, cadmium naphthenate, mercurynaphthenate, indium naphthenate, or bismuth naphthenate.

DETAILED DESCRIPTION

The following description is presented with a combination of specificembodiments, and it should be noted that descriptions and embodimentsgiven herein are merely for the purposes of describing the specificembodiments of the present disclosure, to make features of theembodiments of the present disclosure more readily understood, and arenot intended to be limiting the scope of the claims.

Unless otherwise specified, the term “aliphatic”, “alicyclic”, and“aromatic” in the present disclosure include but not limited to linear,branched, or cyclic groups, being unsubstituted, substituted by one ormore heteroatoms, or substituted by one or more groups having aheteroatom. Wherein, “aliphatic” and “alicyclic” groups may be saturatedor unsaturated, such as an olefine, a cycloolefine, a diolefin, acyclodiolefin, an alkyne, a cycloalkyne, and a polycyclic hydrocarbon.Aromatic groups may refer to a system having at least one aromatic ring,i.e., a pure aromatic compound such as benzene, naphthalene andanthracene, or an aromatic compound having an aliphatic group, such astoluene, styrene and phenylethyne. The pure aromatic compound, having amonocycle aromatic compound and a fused ring aromatic compound, may bean aromatic hydrocarbon, such as benzene, naphthalene, and anthracene,or may be an aromatic system having heteroatoms, such as pyridine,furan, and thiophene.

The heteroatom or the group having a heteroatom may include but notlimited to a halogen (—F, —Cl, —Br, —I), hydroxyl (—OH), carboxyl(—COOH), acyl (—CO—), acyloxy (—COO—), amino (—NH₂), alkylamino (—NHR),dialkylamino (—NR₁R₂), arylamino (—NHAr), amide (—CONH₂), ester (—COOR),carboxamide (—CONR₁R₂), carbamate (—NHCOOR), alkoxyl (—OR), aryloxy(—OAr), alkylthio (—SR), arylthio (—SAr), alkyl sulfonate (—OSO₂R),nitro (—NO₂), cyano (—CN), isocyano (—NC), oxo (═O), azo (—N═N—), thiol(—SH), sulfonyl (—SO₂R), phosphono (—PO(OR₁)(OR₂)), phosphinyl

a thioester (—NCS), thioalkoxy (—OCSR), thiocyanate (—SCN),isothiocyanate (—NCS), a phosphate ester or salt (—OP(O)(OH)₂), asulfate ester or salt (—OSO₂(OH)), or a combination thereof.

Herein, an alkyl, cycloalkyl, and aryl should be explained as below. Asappreciated by those skilled in the art, the alkyl may refer to asaturated hydrocarbon group which is formed by removing a hydrogen atomfrom an alkane molecule, such as methyl, methylene, ethyl, or isopropyl;the cycloalkyl may refer to the general term for hydrocarbon groupsformed by a removal of a hydrogen atom from a saturated hydrocarbonhaving an alicyclic structure, for example, a monocyclic alicyclichydrocarbon and a fused ring alicyclic hydrocarbon, such as cyclobutylor cyclopentyl; the aryl may refer to the general term of groups formedby removing a hydrogen atom from an aromatic nucleus or other carbonatom of any aromatic hydrocarbon molecules, such as phenyl, o-tolyl,1-naphthyl (or α-naphthyl), 2-naphthyl (or β-naphthyl), benzyl, orphenylethyl.

A monovalent hydrocarbon group may refer to a group formed by a removalof a hydrogen atom in hydrocarbons, such as methyl (—CH₃), ethyl(—CH₂CH₃), phenyl (—C₆H₅); a bivalent hydrocarbon group may refer to agroup formed by a removal of two hydrogen atoms in hydrocarbons, such asmethylene (—CH₂—), ethylidene (—CH₂CH₂—), or p-phenylene (-p-C₆H₄—).Similarly, valences of other functional groups also have the samemeaning, for example, nitro is monovalent (—NO₂), and oxo is divalent(═O).

According to some embodiments of the present disclosure, the structuralframework of the antibacterial compound may include a quaternaryammonium group with a positive charge, the group having a goodantibacterial property, and in order to make the whole compoundelectrically neutral, the structure of the antibacterial compound mayalso include a group with a negative charge, the group being attached tothe main framework. In addition, the compound may further include anisocyanate group at the end of the molecule, and the compound may bebound to materials such as polymeric fibers and natural fibers byreacting the isocyanate group with a functional group in the materials.

According to one aspect of the present disclosure, a preparation methodfor the antibacterial compound may include the following steps:

React tertiary amine represented by the general formula (III) with areactant B represented by the general formula (IV), and generate amixture;

wherein, the Y represents —OH, —NH₂, or —SH; R′ represents a divalentalkyl, cycloalkyl, or aryl having from 1 to 18 carbon atoms, optionallysubstituted by at most 18 heteroatoms; R₂ and R₃ independently for eachoccurrence represent a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 18 carbon atoms; L represents adivalent unsubstituted or substituted alkyl, cycloalkyl, or aryl havingfrom 1 to 18 carbon atoms; and D represents —COOH or —NCO.

In this reaction, a typical nucleophilic addition reaction may occurbetween the functional group Y (—OH, —SH, or —NH₂) in the tertiary aminerepresented by the general formula (III) and the isocyanate functionalgroup (—NCO) in the reactant B represented by the general formula (IV),and generate a carbamate, thiocarbamate or urea structure. The reactantB may include an isocyanate functional group and another isocyanatefunctional group or carboxyl group (functional group D). In the firststep of the reaction, the isocyanate functional group in the compoundrepresented by the general formula (III) may react with the functionalgroup Y in the compound represented by the general formula (IV), and thefunctional group D is reserved at one end.

It should be understood that a similar antibacterial compound having aterminal isocyanate can be obtained via the above reaction through anycompound having at least two isocyanates. Since a polyisocyanatecompound may include a plurality of isocyanates, only one of theplurality of isocyanates in a molecule is reacted, and other isocyanatesare reserved in the final antibacterial compound when a nucleophile isnot excessive. The number of carbon atoms or the molecular weight of thepolyisocyanate compound has no effect on the reaction, as long as anucleophilic addition reaction can occur between the polyisocyanatecompound and the nucleophile. The polyisocyanate may be a aliphaticpolyisocyanate, an alicyclic polyisocyanate, a heterochainpolyisocyanate, an aromatic polyisocyanate, a substituted aliphatic oralicyclic or heterocyclic polyisocyanate, wherein the substituent mayinclude but not limited to —F, —Cl, —Br, —I, —OCH₃, —OCH₂CH₃, —OPr, —CN,—SCN, —NO, —NO₂, etc. As is well known to those skilled in the art, thepolyisocyanate compound may often present in a form of a dimer, atrimer, or other polymers, accordingly, the polyisocyanate herein mayalso include a monomer, a dimer, a trimer or other oligomers thereof.

The aliphatic polyisocyanate may include but not limited tohexamethylene diisocyanate, tetramethylene diisocyanate,1,8-octamethylene diisocyanate, 1,10-decamethylene diisocyanate,1,12-dodecamethylene diisocyanate, 1,14-tetradecylmethylenediisocyanate, a derivative of lysine diisocyanate, trimethylhexanediisocyanate, tetramethylhexane diisocyanate, and a dimer, a trimer, andother oligomers thereof.

The alicyclic or heterocyclic polyisocyanate may include but not limitedto 1,4-, 1,3- or 1,2-diisocyanate cyclohexane, 4,4- or 2,4-di(isocyanatecyclohexyl)methane,1-isocyanate-3,3,5-trimethyl-5-(isocyanatemethyl)cyclohexane(isophoronediisocyanate), 1,3- or 1,4-di(isocyanatemethyl)cyclohexane, 2,4- or2,6-diisocyanate-1-methylcyclohexane, a 3(or 4),8(or 9)-di(isocyanatemethyl)tricyclo[5.2.1.0.2.6]decane isomer mixture, norborenediisocyanate, 4,5-di(isocyanatomethyl)-1,3-dithiolane, and a dimer, atrimer, and other oligomers thereof.

The heterochain polyisocyanate may include but not limited todi(isocyanatomethylthio)methane, di(isocyanatomethylthio)methylthiomethane, di(2-isocyanatoethylthio)methane,di(3-isocyanatopropylthio)methane, di(isocyanato methylthio)phenylmethane, di(2-isocyanatoethylthio)phenyl methane,di(3-isocyanatopropylthio)phenyl methane,1,2-(diisocyanatoethylthio)ethane,1-isocyanatomethylthio-2-(2-isocyanatoethylthio)ethane,1-isocyanatoethylthio-2-(3-isocyanatopropylthio)ethane,di(isocyanatomethylthioethyl)sulfoether,tetra(isocyanatomethylthio)-1,4-dithiane,2,2,5,5-tetra(isocyanatomethylthio)-1,3-dithiane, tri(isocyanatomethylthio)methane, and a dimer, a trimer, and other oligomers thereof.

The aromatic polyisocyanate may include but not limited to toluenediisocynate, diphenylmethane diisocyanate, o-xylene diisocyanate,m-xylene diisocyanate, p-xylene diisocyanate,α,α,α′,α′-tetramethyl-p-xylene diisocyanate,1,3,5-tri(isocyanatomethyl)benzene, 4-methyl m-xylene diisocyanate,4-ethyl m-xylene diisocyanate, 1,5-naphthalene diisocyanate, and adimer, a trimer, and other oligomers thereof; 4-chloro m-xylenediisocyanate, 4,5-dichloro m-xylene diisocyanate, 2,3,5,6-tetrabromop-xylene diisocyanate, and a dimer, a trimer, and other oligomersthereof.

In some embodiments, the isocyanate structure may also be a terminalisocyanate organic compound having at least one carboxyl (—COOH), abackbone structure of the organic compound may include an unsubstitutedor substituted aliphatic, alicyclic, heterochain, heterocyclic, aromaticstructure, wherein the substituent may include but not limited to —F,—Cl, —Br, —I, —OCH₃, —OCH₂CH₃, —OPr, —CN, —SCN, —NO, —NO₂, etc.

Taking a reaction of dimethyl ethanolamine and tetramethylenediisocyanate as an example, when the two reactants react in a molarratio of 1:1, the reaction formula is as follows:

As for the amine used in the first step of the reaction, tertiary aminehaving a highly nucleophilic group Y, such as a hydroxyl, a thiol, or anamino (—NH₂), may be needed. Wherein, the function of the group Y is toattack the carbon atom of the isocyanate through lone pair electronscarried by oxygen, sulfur, and nitrogen atoms, so as to couple with theisocyanate. Since the amine compound may also couple with the isocyanatethrough a nitrogen atom, which may compete with the group Y in reactingwith the isocyanate, so that tertiary amine with lower reactive activityis needed here. With a larger steric hindrance, the nitrogen atom in thetertiary amine may be more difficult to couple with the isocyanate.

Exemplary tertiary amine having a nucleophilic group may include but notlimited to N,N-dimethyl ethanolamine, N,N-diethyl ethanolamine,N,N-dimethyl ethylenediamine, N,N-di-n-propyl ethanolamine,N,N-diisopropyl ethanolamine, N,N-di-n-butyl ethanolamine,N,N-di-n-pentyl ethanolamine, N,N-dicyclohexyl ethanolamine,dimethylamino methanthiol, dimethylamino ethanethiol, or3,3′-iminobis(N,N-dimethyl propylamine).

In the presence of an alkaline reagent (such as tertiary amine,phosphines), the hydrogen atom in the Y functional group may also beremoved in the form of a hydrogen ion, the nucleophilicity of O, S, andN atoms in the Y functional group may further be improved, so that thealkaline reagent may be used as a catalyst. While, in the presence of aLewis acid such as a metal ion and an organometallic compound, theoxygen atom in the isocyanate may form a coordination bond with theLewis acid, a part of electrons are transferred onto the metal atom fromthe oxygen atom, so that the electropositivity of the carbon atom in theisocyanate may be further enhanced, which facilitates receiving anattack from the nucleophile, and thus the Lewis acid may be used as acatalyst.

In a preparation using a catalyst, preferably, the catalyst may be one,two, or a combination of an organic amine compound, a phosphoruscompound, and a metal-containing catalyst.

The organic amine compound may be classified to several categories:aliphatic amines, such as N,N-dimethyl cyclohexane, bis(2-dimethylaminoethyl)ether, N,N,N′,N′-tetramethyl alkylene diamine, triethylamine, orN,N-dimethyl benzylamine; alicyclic amines, such as triethylene diamine(DABCO), N-ethyl morpholine, N-methyl morpholine, N,N′-diethylpiperazine, or dimethylamino cyclohexane; and aromatic amines, such asN,N-dimethyl aniline, pyridin, or 4-dimethylamino pyridine (N,N-dimethylpyridine). A common property of the amine compounds may include thatthey are all alkaline and may accelerate the reaction. Meanwhile, theamine compounds all include a tertiary nitrogen atom or a pyridinenitrogen atom, and thus cannot react with the isocyanate.

Similar to the amine compounds, the phosphorus compounds may alsofunction as an alkaline and accelerate the reaction. The phosphoruscompounds may include but not limited to various tertiary phosphines inwhich three organic groups substituting three hydrogen atoms may becompletely the same or completely different. Tertiary phosphinessubstituted by three same organic groups may include but not limited totriphenyl phosphine, trimethyl phosphine, triethyl phosphine,tri-n-propyl phosphine, triisopropyl phosphine, tri-n-butyl phosphine,or tri-t-butyl phosphine. Tertiary phosphines substituted by threedifferent organic groups may include but not limited to dimethyl phenylphosphine, methyl diphenyl phosphine, diethyl phenyl phosphine, or ethyldiphenyl phosphine.

In the metal-containing catalyst, since the metal ion may generally bindto the oxygen atom in the isocyanate to form a complex, electrons in theoxygen atom may transfer onto the metal atom, which enhances theelectropositivity of the carbon atom bound thereto, facilitating thecarbon atom receiving an attack from the nucleophile. Themetal-containing catalyst may include but not limited to an inorganicmetal salt, carboxylate, phenolate, metal alkylates, wherein carboxylatemay be classified to linear or branched carboxylate and cyclicnaphthenate. The metal elements contained are mainly alkali metals(lithium, sodium, potassium, rubidium, cesium, etc.); alkali earthmetals (magnesium, calcium, strontium, barium); transition metals(uranium, cerium, titanium, zirconium, vanadium, chromium, molybdenum,manganese, ferrum, cobalt, nickel, copper, zinc, cadmium, mercury,etc.), aluminum, gallium, indium, thallium, tin, plumbum, stibium,bismuth, etc., but not limited thereto.

Common metal-containing catalysts may include but not limited to lithiumacetate, lithium octanoate, lithium naphthenate, sodium trichlorphenate,sodium stearate, potassium acetate, potassium octanoate, calciumacetate, calcium octanoate, strontium naphthenate, barium acetate,uranyl nitrate, cerium nitrate, titanium tetrachloride, dibutyl titaniumdichloride, titanium tetrabutyl, butoxy titanium trichloride, zirconiumnaphthenate, zirconium octanoate, vanadium trichloride, chromiumnaphthenate, molybdenum hexacarbonyl, manganese octanoate, ferrictrichloride, ferrum octanoate, ferrum triacetylacetonate, ferrocene,cobalt octanoate, cobalt naphthenate, cobalt linoleate, cobalt benzoate,nickelocene, nickel octanoate, nickel naphthenate, copper acetate,copper octanoate, copper naphthenate, zinc octanoate, zinc naphthenate,cadmium nitrate, cadmium naphthenate, mercury diphenyl, mercurynaphthenate, aluminum triphenyl, aluminium stearate, gallium acetate,indium naphthenate, thallium octanoate, tin tetrachloride, tintetrachloride, etrabutyl tin, tributyl tin chloride, dibutyl tindichloride, butyl tin trichloride, tributyl tin cyanide, dibutyl tindilaurate, dibutyl tin diacetate, dibutyl tin dioctoate, tributyl tinoctoate, diphenyl tin dioctoate, dibutyl tin dibutoxy, dibutyl tinbis(acetylacetoate), dibutyl tin bis(isooctylmaleate), dioctoate tinoxide, dibutyl tin sulfide, stannous oleate, stannous tartrate, plumbousbenzoate, stannous octoate, plumbous octanoate, plumbous oleate, leadnaphthenate, antimony trichloride, antimony pentachloride, triphenylstibium dichloride, triphenyl stibium, bismuth naphthenate, and diethylbismuth acetate.

Preferably, the catalyst is a metal-containing catalyst. Morepreferably, the metal-containing catalyst represents at least one of tintetrachloride, tetrabutyl tin, tributyl tin chloride, butyl tindichloride, butyl tin trichloride, tributyl tin cyanide, dibutyl tindiacetate, dibutyl tin dioctanoate, tributyl tin octanoate, diphenyl tindioctanoate, dibutoxy dibutyl tin, dibutyl tin bis(acetylacetoate),dibutyl tin bis(isooctylmaleate), dioctanoate tin oxide, dibutyl tinsulfide, stannous oleate, stannous tartrate, dibutyl tin dilaurate,stannous octanoate, or metal naphthenate. More preferably, themetal-containing catalyst may be metal naphthenate. More preferably, thenaphthenate metal represents at least one of copper naphthenate, zincnaphthenate, lead naphthenate, lithium naphthenate, cobalt naphthenate,nickel naphthenate, cadmium naphthenate, mercury naphthenate, indiumnaphthenate, or bismuth naphthenate.

In some embodiments, the catalyst may not be added, and the reactant Bmay directly react with the tertiary amine or pyridine substituted by aterminal amino, a terminal hydroxyl or a terminal thiol.

React the mixture with a reactant A, and generate the antibacterialcompound;

wherein, the reactant A represents propane sultone, butane sultone,β-propiolactone, X(CH₂)_(v)CO₂—Mt⁺, X(CH₂)vSO₃—Mt⁺, or cyclic phosphateester, the X represents Br, Cl, or I, v is an integer greater than 0,Mt⁺ represents Li⁺, Na⁺, K⁺, NH₄ ⁺, Ag⁺, ½Mg²⁺, or ½Ca²⁺, and the cyclicphosphate ester represents:

wherein, R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms; and R₆ represents adivalent unsubstituted or substituted alkyl having from 1 to 6 carbonatoms.

In the reactant A, since the carbon atom bound to the oxygen atom inpropane sultone and butane sultone is liable to receive an attack from anucleophile, while the mixture generated in the first step of thereaction include a tertiary amine nitrogen atom with goodnucleophilicity, a ring-opening reaction can occur between the reactantA and the mixture generated in the first step of the reaction, forming aC—N bond. Therefore, a linking group is added to the tertiary nitrogenatom in the tertiary amine and form a quaternary ammonium group, whichforms a zwitterionic compound together with a sulphonic acid group.

When the reactant A is cyclic phosphate ester (e.g.,2-ethoxy-2-oxy-1,3,2-dioxaphospholane, i.e., EOP), the carbon atom boundto the oxygen atom in the ring may receive an attack from the tertiarynitrogen atom, and a ring-opening reaction may occur, so that thetertiary nitrogen atom become a quaternary ammonium group which forms azwitterionic compound together with a phosphoric acid group.Additionally, rings in the propiolactone and butyrolactone may also beliable to be opened due to a large ring strain and a small atom number,so that a ring-opening reaction may also occur in the presence of thetertiary nitrogen atom with strong nucleophilicity, forming a quaternaryammonium group and generating a carboxyl, and a zwitterionic compoundmay be formed.

Similarly, in X(CH₂)_(v)CO₂ ⁻Mt⁺ and X(CH₂)_(v)SO₃ ⁻Mt⁺, since X(halogen such as Cl, Br, I) atom has large electronegativity and thebond formed with the carbon atom is weak, the X is easier to leave, thecarbon atom bound thereto is liable to be attacked by the nucleophile,so that a C—N bond may be formed under an attack of the tertiarynitrogen atom, forming a quaternary ammonium group, which forms azwitterionic compound together with a carboxyl or sulphonic acid group.Similarly, a similar nucleophilic substitution reaction may occur inmetal carboxylate substituted by other leaving groups including but notlimited to p-tosyl (—OTs), mesyl (—OMs) or trifluoromesyl (—OTf).

A solvent for preparing the antibacterial compound may include but notlimited to organic solvents such as ethers, ketones, aromatic compounds,nitriles, esters or amides. A solvent itself may also be a mixture ofseveral solvents, e.g., a mixture of two or more solvents. The solventmay be chosen according to a reactant solubility, a temperature ofreaction, and a chemical reactivity of the solvent. Generally, a solventeasy to react with —N═C═O, such as water, alcohols, amines or carboxylicacid, is not suitable as a solvent for this reaction. Therefore, thesolvent used in this embodiment needs to be previously dewatered,alcohol removed, and the like.

More preferably, the ether solvent may be THF, 1,4-dioxan ring, glycoldimethyl ether or tetrahydropyrane, etc.; the ketone solvent may beacetone, butanone, cyclohexanone, hypnone or phorone, etc.; the aromaticcompounds may be toluene, pyridine or imidazole, etc.; esters may beethyl acetate, n-propyl acetate, n-butyl acetate, methyl formate orethyl formate, etc.; nitriles may be acetonitrile, propionitrile orbenzonitrile, etc.; amides may be N-methylpyrrolidone,N,N-dimethylformamide or N,N-dimethylacetamide etc. The above is merelyan example of a common solvent that can be used in this reaction and isnot intended to limit the scope of the solvent.

In fact, any aprotic solvent which can dissolve the reaction rawmaterials may be used as a reaction solvent, e.g., ethylene carbonateand trimethylene carbonate.

The stirring method used in preparing the antibacterial compound may bea mechanical or magnetic stirring method in which the reactants can besufficiently contacted.

The addition of the reactant solution may be manually dropping ordropping using a mechanical drip machine, and the dropping speed may beconstant or may be continuously changed as the reaction progresses.

As for separation of the final product, different separation methods maybe used according to different forms of the final product, as anon-precipitate, the final product can be purified by extraction ordistillation; as a precipitate, the final product can be purified bycentrifugation, filtration, and the like.

According to another aspect of the present disclosure, a method forpreparing the antibacterial compound may include the following steps:

1) React pyridine represented by the general formula (V) with a reactantB represented by the general formula (IV), and generate a mixture;

Wherein, the Q represents —OH, —NH₂, or —SH; G′ represents a divalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to18 carbon atoms; G₂ and G₃ independently for each occurrence represent—H, —F, —Cl, —Br, —I, —OCH₃, —OCH₂CH₃, —OPr, —CN, —SCN, —NO, —NO₂, amonovalent unsubstituted or substituted alkyl, cycloalkyl, or arylhaving from 1 to 7 carbon atoms; D represents —COOH or —NCO; and Lrepresents a divalent unsubstituted or substituted alkyl, cycloalkyl, oraryl having from 1 to 18 carbon atoms.

In this reaction, a typical nucleophilic addition reaction may occurbetween the functional group Q (—OH, —SH, —NH₂) in the pyridinerepresented by the general formula (V), and the isocyanate functionalgroup (—NCO) in the reactant B represented by the general formula (IV),and generate a carbamate, thiocarbamate or urea structure. In thereaction, an atom (O, S, N) with large electronegativity in thefunctional group Q includes lone pair electrons, and the carbon atom inthe isocyanate functional group is liable to have an additive reactionwith a nucleophile, due to lack of electrons, to form a carbamate,thiocarbamate or urea structure.

In the presence of an alkaline reagent (such as tertiary amine,phosphines), the hydrogen atom in the Q functional group may also beremoved in the form of a hydrogen ion, the nucleophilicity of O, S, andN atoms in the Q functional group may be further improved, so that thealkaline reagent may be used as a catalyst. While, in the presence of aLewis acid such as a metal ion and an organometallic compound, theoxygen atom in the isocyanate may form a coordination bond with theLewis acid, a part of electrons are transferred onto the metal atom fromthe oxygen atom, so that the electropositivity of the carbon atom in theisocyanate may be further enhanced, which facilitates receiving anattack from the nucleophile, and thus the Lewis acid may be used as acatalyst.

In a preparation using a catalyst, preferably, the catalyst may be one,two, or a combination of an organic amine compound, a phosphoruscompound, and a metal-containing catalyst.

The organic amine compound may be classified to several categories:aliphatic amines, such as N,N-dimethyl cyclohexane, bis(2-dimethylaminoethyl)ether, N,N,N′,N′-tetramethyl alkylene diamine, triethylamine, orN,N-dimethyl benzylamine; alicyclic amines, such as triethylene diamine(DABCO), N-ethyl morpholine, N-methyl morpholine, N,N′-diethylpiperazine, or dimethylamino cyclohexane; and aromatic amines, such asN,N-dimethyl aniline, pyridin, or 4-dimethylamino pyridine (N,N-dimethylpyridine). A common property of the amine compounds include that theyare all alkaline and may accelerate the reaction. Meanwhile, the aminecompounds all include a tertiary nitrogen atom or a pyridine nitrogenatom, and thus do not include an active N—H or O—H bond and cannot reactwith the isocyanate.

Similar to the amine compounds, the phosphorus compounds may alsofunction as an alkaline and accelerate the reaction. The phosphoruscompounds may include but not limited to various tertiary phosphines inwhich three organic groups substituting three hydrogen atoms may becompletely the same or completely different. Tertiary phosphinessubstituted by three same organic groups may include but not limited totriphenyl phosphine, trimethyl phosphine, triethyl phosphine,tri-n-propyl phosphine, triisopropyl phosphine, tri-n-butyl phosphine,or tri-t-butyl phosphine. Tertiary phosphines substituted by threedifferent organic groups may include but not limited to dimethyl phenylphosphine, methyl diphenyl phosphine, diethyl phenyl phosphine, or ethyldiphenyl phosphine.

In the metal-containing catalyst, since the metal ion may generally bindto the oxygen atom in the isocyanate to form a complex, electrons in theoxygen atom may transfer onto the metal atom, which enhances theelectropositivity of the carbon atom bound thereto, facilitating thecarbon atom receiving an attack from the nucleophile. Themetal-containing catalyst may include but not limited to an inorganicmetal salt, carboxylate, phenolate, metal alkylates, wherein carboxylatemay be classified to linear or branched carboxylate and cyclicnaphthenate. The metal elements contained are mainly alkali metals(lithium, sodium, potassium, rubidium, cesium, etc.); alkali earthmetals (magnesium, calcium, strontium, barium); transition metals(uranium, cerium, titanium, zirconium, vanadium, chromium, molybdenum,manganese, ferrum, cobalt, nickel, copper, zinc, cadmium, mercury,etc.), aluminum, gallium, indium, thallium, tin, plumbum, stibium,bismuth, etc., but not limited thereto.

Common metal-containing catalysts may include but not limited to lithiumacetate, lithium octanoate, lithium naphthenate, sodium trichlorphenate,sodium stearate, potassium acetate, potassium octanoate, calciumacetate, calcium octanoate, strontium naphthenate, barium acetate,uranyl nitrate, cerium nitrate, titanium tetrachloride, dibutyl titaniumdichloride, titanium tetrabutyl, butoxy titanium trichloride, zirconiumnaphthenate, zirconium octanoate, vanadium trichloride, chromiumnaphthenate, molybdenum hexacarbonyl, manganese octanoate, ferrictrichloride, ferrum octanoate, ferrum triacetylacetonate, ferrocene,cobalt octanoate, cobalt naphthenate, cobalt linoleate, cobalt benzoate,nickelocene, nickel octanoate, nickel naphthenate, copper acetate,copper octanoate, copper naphthenate, zinc octanoate, zinc naphthenate,cadmium nitrate, cadmium naphthenate, mercury diphenyl, mercurynaphthenate, aluminum triphenyl, aluminium stearate, gallium acetate,indium naphthenate, thallium octanoate, tin tetrachloride, tintetrachloride, tetrabutyl tin, tributyl tin chloride, dibutyl tindichloride, butyl tin trichloride, tributyl tin cyanide, dibutyl tindilaurate, dibutyl tin diacetate, dibutyl tin dioctoate, tributyl tinoctoate, diphenyl tin dioctoate, dibutyl tin dibutoxy, dibutyl tinbis(acetylacetoate), dibutyl tin bis(isooctylmaleate), dioctoate tinoxide, dibutyl tin sulfide, stannous oleate, stannous tartrate, plumbousbenzoate, stannous octoate, plumbous octanoate, plumbous oleate, leadnaphthenate, antimony trichloride, antimony pentachloride, triphenylstibium dichloride, triphenyl stibium, bismuth naphthenate, and diethylbismuth acetate.

Preferably, the catalyst is a metal-containing catalyst. Morepreferably, the metal-containing catalyst represents at least one of tintetrachloride, tetrabutyl tin, tributyl tin chloride, butyl tindichloride, butyl tin trichloride, tributyl tin cyanide, dibutyl tindiacetate, dibutyl tin dioctanoate, tributyl tin octanoate, diphenyl tindioctanoate, dibutoxy dibutyl tin, dibutyl tin bis(acetylacetoate),dibutyl tin bis(isooctylmaleate), dioctanoate tin oxide, dibutyl tinsulfide, stannous oleate, stannous tartrate, dibutyl tin dilaurate,stannous octanoate, or metal naphthenate. More preferably, themetal-containing catalyst may be metal naphthenate. More preferably, thenaphthenate metal represents at least one of copper naphthenate, zincnaphthenate, lead naphthenate, lithium naphthenate, cobalt naphthenate,nickel naphthenate, cadmium naphthenate, mercury naphthenate, indiumnaphthenate, or bismuth naphthenate.

In some embodiments, the catalyst may not be added, and the reactant Bmay directly react with the tertiary amine or pyridine substituted by aterminal amino, a terminal hydroxyl or a terminal thiol.

In the first step of the reaction, the nitrogen atom in the pyridinecompound does not participate in the reaction. The function of thepyridine compound lies in that, firstly it provide a nucleophilicfunctional group Q to react with the reactant B having the isocyanate;secondly, the pyridine nitrogen atom in the pyridine compound is theparent of the quaternary ammonium salt in the final antibacterialcompound, and the pyridine nitrogen atom may become a quaternarynitrogen atom, i.e. a pyridine quaternary ammonium salt structure, dueto a new formation of a C—N bond in the subsequent synthesis. The numberof carbon atoms in the pyridine compound has no effect on the reaction,as long as the pyridine compound include a group that can react with theisocyanate, such as a hydroxyl, a thiol or an amino, i.e. the first stepof the reaction may take place.

A common property of the pyridine for preparing the antibacterialcompound lies in that they all include one or more groups having anactive hydrogen atom, such as a hydroxyl, an amino, and thiol, by whichthe pyridine compound can react with the isocyanate to couple with thesame.

Exemplary pyridine may include but not limited to4-hydroxymethylpiperidine, 4-aminopyridine, 4-mercaptopyridine or2,6-dimethyl-4-aminopyridine. The hydrogen atom in the pyridine ring maybe substituted by a substituent such as halogen (—F, —Cl, —Br, —I) orpseudohalogen (—CN, —SCN, —OCN, etc.), an alkoxyl (—OCH₃, —OCH₂CH₃,—OPr), —NO or NO₂, or an alkyl having from 1 to 7 carbon atoms or anaryl, the number of substitutes being at most 7.

2) React the mixture with a reactant A, and generate the antibacterialcompound;

The reactant A represents propane sultone, butane sultone,β-propiolactone, X(CH₂)_(v)CO₂—Mt⁺, X(CH₂)vSO₃—Mt⁺, or cyclic phosphateester, the X represents Br, Cl, or I, v is an integer greater than 0,Mt⁺ represents Li⁺, Na⁺, K⁺, NH₄ ⁺, Ag⁺, ½Mg²⁺, or ½Ca²⁺, and the cyclicphosphate ester represents:

wherein, R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms; and R₆ represents adivalent unsubstituted or substituted alkyl having from 1 to 6 carbonatoms.

In the reactant A, since the carbon atom bound to the oxygen atom insultone is liable to receive an attack a the nucleophile, while themixture generated in the first step of the reaction include a tertiarynitrogen atom with good nucleophilicity, a ring-opening reaction canoccur between the reactant A and the mixture generated in the first stepof the reaction, forming a C—N bond. Therefore, a linking group is addedto the tertiary nitrogen atom in the tertiary amine and form aquaternary ammonium group, which forms a zwitterionic compound togetherwith a sulphonic acid group. Similar to sultone, the carbon atom boundto the oxygen atom in the cyclic phosphate ester may receive an attackfrom the tertiary nitrogen atom and a ring-opening reaction may occur,so that the tertiary nitrogen atom become a quaternary ammonium groupwhich forms a zwitterionic compound together with a phosphoric acidgroup. Additionally, rings in the propiolactone and butyrolactone mayalso be liable to be opened due to a large ring strain and a small atomnumber, so that a ring-opening reaction may also occur in the presenceof the tertiary nitrogen atom with strong nucleophilicity, forming aquaternary ammonium group and generating a carboxyl, and thus azwitterionic compound is formed. In X(CH₂)_(v)CO₂ ⁻Mt⁺ and X(CH₂)_(v)SO₃⁻Mt⁺, since X (halogen such as Cl, Br, I) atom has largeelectronegativity and the bond formed with the carbon atom is weak, theX is easier to leave, the carbon atom bound thereto is liable to beattacked by the nucleophile, so that a C—N bond may be formed under anattack of the tertiary nitrogen atom, forming a quaternary ammoniumgroup, which forms a zwitterionic compound together with a carboxyl orsulphonic acid group. Similarly, a similar nucleophilic substitutionreaction may occur in metal carboxylate substituted by other leavinggroups including but not limited to p-tosyl (—OTs), mesyl (—OMs) ortrifluoromesyl (—OTf).

A solvent for preparing the antibacterial compound may include but notlimited to organic solvents such as ethers, ketones, aromatic compounds,nitriles, esters or amides. A solvent itself may also be a mixture ofseveral solvents, e.g., a mixture of two or more solvents. The solventmay be chosen according to a reactant solubility, a temperature ofreaction, and a chemical reactivity of the solvent. Generally, a solventeasy to react with —N═C═O, such as water, alcohols, amines or carboxylicacid, is not suitable as a solvent for this reaction. Therefore, thesolvent used in this embodiment needs to be previously dewatered,alcohol removed, and the like.

More preferably, the ether solvent may be THF, 1,4-dioxan ring, glycoldimethyl ether or tetrahydropyrane, etc.; the ketone solvent may beacetone, butanone, cyclohexanone, hypnone or phorone, etc.; the aromaticcompounds may be toluene, pyridine or imidazole, etc.; esters may beethyl acetate, n-propyl acetate, n-butyl acetate, methyl formate orethyl formate, etc.; nitriles may be acetonitrile, propionitrile orbenzonitrile, etc.; amides may be N-methylpyrrolidone,N,N-dimethylformamide or N,N-dimethylacetamide etc. The above is merelyan example of a common solvent that can be used in this reaction and isnot intended to limit the scope of the solvent.

The above is merely an example of a common solvent that can be used inthis reaction and is not intended to limit the scope of the solvent. Infact, any aprotic solvent which can dissolve the reaction raw materialsmay be used as a reaction solvent, e.g., ethylene carbonate andtrimethylene carbonate.

The stirring method used in preparing the antibacterial compound may bea mechanical or magnetic stirring method in which the reactants can besufficiently contacted.

The addition of the reactant solution may be manually dropping ordropping using a mechanical drip machine, and the dropping speed may beconstant or may be continuously changed as the reaction progresses.

As for separation of the final product, different separation methods maybe used according to different forms of the final product; as anon-precipitate, the final product can be purified by extraction ordistillation; as a precipitate, the final product can be purified bycentrifugation, filtration, and the like.

Raw materials and other chemical agents used in the following examplesare commercially available. If necessary, the raw materials and otherchemical agents may be purified by methods known in the art, such asremoval of water, oxidized components, primary and secondary amines intertiary amines, etc., which can be carried out by means ofdistillation, splitting, extraction, or addition of reagents.

Example 1

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) represented by:

was weighted and added to a round flask with mechanical stirring. Afteradding a catalyst of 0.2 ml dibutyl tin dilaurate (DBTDL), 17.8 g (0.2mol) dimethyl ethanolamine (HOCH₂CH₂N(CH₃)₂) was slowly dropwise addedthereto, using a dropping funnel under stirring at the temperature of30° C. After the dropwise addition, the reaction was continued for 1 h,and the stirring was continued for 12 h at this temperature. Then, 24.4g (0.2 mol) propane sultone (hereinafter referred to as 1,3-PS, with astructure as follows),

dissolved in 400 mL anhydrous THF was dropwise added. After the dropwiseaddition, the reaction was continued for 1 h and generate a precipitate,which was centrifuged and purified for several times to afford theantibacterial compound having a terminal isocyanate according to theexample.

In this example, isophorone diisocyanate was used as a reactant havingthe isocyanate. It should be understood that a similar antibacterialcompound having a terminal isocyanate can be obtained via the abovereaction through any compound having at least two isocyanates. Since apolyisocyanate compound may include a plurality of isocyanates, only oneisocyanate of the plurality of isocyanates in a molecule is reacted, andother isocyanates are reserved in the final antibacterial compound whena nucleophile is not excessive. The number of carbon atoms or themolecular weight of the polyisocyanate compound has no effect on thereaction, as long as a nucleophilic addition reaction can occur betweenthe polyisocyanate compound and the nucleophile. In this example, theisocyanate structure may also be a terminal isocyanate organic compoundhaving at least one carboxyl, a backbone structure of the organiccompound may include an unsubstituted or substituted aliphatic,alicyclic, heterochain, heterocyclic, aromatic structure, wherein thesubstituent may include but not limited to —Cl, —Br, —I, —OCH₃,—OCH₂CH₃, —OPr, —CN, —SCN, —NO, —NO₂, etc.

In the reaction, the function of propane sultone is to open afive-membered ring by receiving a nucleophilic attack from the tertiaryamine N atom and thus to form a sulphonic acid group, meanwhile forminga quaternary ammonium group. Since the carbon atom bound to the oxygenatom in sultone is liable to receive an attack from the nucleophile,while the mixture generated in the first step of the reaction includes atertiary nitrogen atom with good nucleophilicity, a ring-openingreaction can occur between the reactant A and the mixture generated inthe first step of the reaction, forming a C—N bond. Therefore, a linkinggroup is added to the tertiary nitrogen atom in the tertiary amine toform a quaternary ammonium group, which forms a zwitterionic compoundtogether with a sulphonic acid group. Similarly, other sultones such asbutane sultone and ethane sultone may also be used in the second step ofthe reaction since a similar reaction may take place.

Although dibutyl tin dilaurate was used as a catalyst in this example, acatalyst is not always necessary and an organic amine compound havinghigher activity can react directly with a compound having a plurality ofisocyanates in the absence of the catalyst. In a preparation using acatalyst, preferably, the catalyst may be one, two, or a combination ofan organic amine compound, a phosphorus compound, and a metal-containingcatalyst. For example, triethylamine, triphenyl phosphine, dibutyl tindioctanoate.

In some embodiments, the catalyst may not be added, and the reactant Bmay directly react with the tertiary amine or pyridine substituted by aterminal amino, a terminal hydroxyl or a terminal thiol.

In addition to N,N-dimethyl ethanolamine, amines for preparation in thisexample may also be N,N-diethyl ethanolamine, N,N-dimethylethylenediamine, N,N-di-n-propyl ethanolamine, N,N-diisopropylethanolamine, N,N-di-n-butyl ethanolamine, N,N-di-n-pentyl ethanolamine,N,N-dicyclohexyl ethanolamine, or 3,3′-iminobis(N,N-dimethylpropylamine).

Moreover, although amines were used in this example, tertiary amines orpyridine organic compounds having a terminal alcohol group or terminalthiol may be used, such as 4-hydroxymethylpiperidine and2,6-dimethyl-4-aminopyridine.

Example 2

50.1 g (0.2 mol) diphenylmethane diisocyanate (MDI) was weighted andadded to a round flask with mechanical stirring. After adding a catalystof 0.2 ml dibutyl tin dilaurate, 23.5 g (0.2 mol) N,N-diethylethanolamine (HOCH₂CH₂N(CH₂CH₃)₂) was slowly dropwise added thereto,using a dropping funnel under stirring at the temperature of 30° C.After the dropwise addition, the reaction was continued for 1 h, and thestirring was continued for 12 h at this temperature. Then, 24.4 g (0.2mol) propane sultone dissolved in 400 mL anhydrous THF was dropwiseadded. After the dropwise addition, the reaction was continued for 1 hand generate an oil, which was extracted by a polar aprotic solventDMSO, solvent removed, and purified to afford the antibacterial compoundhaving a terminal isocyanate according to this example.

Example 3

33.6 g (0.2 mol) hexamethylene diisocyanate (HDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml stannous octanoate (Sn(CH₃(CH₂)₃CH(C₂H₅)CO₂)₂), 17.8 g (0.2 mol)N,N-dimethyl ethanolamine (HOCH₂CH₂N(CH₃)₂) was slowly dropwise addedthereto, using a dropping funnel under stirring at the temperature of30° C. After the dropwise addition, the reaction was continued for 1 h,and the stirring was continued for 12 h at this temperature. Then, 23.6g (0.2 mol) sodium chloroacetate (ClCH₂CO₂Na) dissolved in 400 mLanhydrous THF was dropwise added. The reaction was continued for 24 hunder the temperature of 20° C. and generate a crude product, which wascentrifuged and purified for several times to afford the antibacterialcompound having a terminal isocyanate according to this example.

In the reaction, the function of sodium chloroacetate is to remove thechlorine atom by receiving a nucleophilic attack from the tertiary amineN atom and thus to form a quaternary ammonium group. Similarly, sodiumcarboxylate substituted by other halogen (Br, I, etc.) or other easilyleaving groups (OTs, OMs, OTf, etc.), such as sodium bromoacetate,sodium iodoacetate, sodium 2-chloropropionate, sodium3-chloropropionate, sodium 2-bromopropionate, sodium 3-bromopropionate,sodium 2-iodopropionate, sodium 3-iodopropionate, or halogenatedcarboxylate with a longer carbon chain, may also be used in the secondstep of the reaction, since the halogen is liable to be removed by thenucleophilic attack from the N atom and thus a similar reaction may takeplace.

The addition of the sodium chloroacetate solution may be manuallydropping or dropping using a mechanical drip machine, and the droppingspeed may be constant or may be continuously changed as the reactionprogresses.

Example 4

34.8 g (0.2 mol) toluene diisocynate (a mixture including 2,4-toluenediisocynate and 2,6-toluene diisocynate) was weighted and added to around flask with mechanical stirring. After adding a catalyst of 0.2 mldibutyl tin dilaurate (DBTDL), 17.8 g (0.2 mol) dimethyl ethanolamine(HOCH₂CH₂N(CH₃)₂) was slowly dropwise added thereto, using a droppingfunnel under stirring at the temperature of 30° C. After the dropwiseaddition, the reaction was continued for 1 h, and the stirring wascontinued for 12 h at this temperature. Then, to the filtrate, 14.4 g(0.2 mol) β-propiolactone represented by:

dissolved in 400 mL anhydrous THF was dropwise added. The reaction wascontinued for 6 h under the temperature of 40° C. to generate a product,which was filtered under normal pressure and purified to afford theantibacterial compound having a terminal isocyanate according to thisexample.

In the reaction, the function of β-propiolactone is to open a ring byreceiving a nucleophilic attack from the tertiary amine N atom and thusto form a carboxyl, meanwhile forming a quaternary ammonium group.Similarly, other lactones, such as β-butyrolactone, γ-butyrolactone,β-valerolactone, γ-valerolactone may also be used in the second step ofthe reaction, since a similar reaction may take place to generate acorresponding zwitterionic compound.

The addition of the β-propiolactone solution may be manually dropping ordropping using a mechanical drip machine, and the dropping speed may beconstant or may be continuously changed as the reaction progresses.

Example 5

52.5 g (0.2 mol) dicyclohexyl methane diisocyanate (HMDI) was weightedand added to a round flask with mechanical stirring. After adding acatalyst of 0.2 ml dibutyl tin dilaurate, 17.8 g (0.2 mol) N,N-dimethylethylenediamine (H₂NCH₂CH₂N(CH₃)₂) was slowly dropwise added thereto,using a dropping funnel under stirring at the temperature of 30° C.After the dropwise addition, the reaction was continued for 1 h, and thestirring was continued for 12 h at this temperature. Then, 24.4 g (0.2mol) propane sultone dissolved in 400 mL anhydrous acetone was dropwiseadded. After the dropwise addition, the reaction was continued for 1 hand generate a precipitate, which was centrifuged and purified forseveral times to afford the antibacterial compound having a terminalisocyanate according to this example.

Example 6

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml dibutyl tin dilaurate, 17.8 g (0.2 mol) N,N-dimethylethylenediamine (H₂NCH₂CH₂N(CH₃)₂) was slowly dropwise added thereto,using a dropping funnel under stirring at the temperature of 30° C.After the dropwise addition, the reaction was continued for 1 h, and thestirring was continued for 12 h at this temperature. Then, to thefiltrate, 14.4 g (0.2 mol) β-propiolactone dissolved in 400 mL anhydrousbutanone was dropwise added. The reaction was continued for 6 h underthe temperature of 40° C. and generate a crude product, which wascentrifuged and purified for several times to afford the antibacterialcompound having a terminal isocyanate.

Example 7

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml dibutyl tin dilaurate, 37.4 g (0.2 mol)3,3′-iminobis(N,N-dimethyl propylamine) represented by:

was slowly dropwise added thereto, using a dropping funnel understirring at the temperature of 30° C. After the dropwise addition, thereaction was continued for 1 h, and the stirring was continued for 12 hat this temperature. Then, 48.8 g (0.4 mol) propane sultone dissolved in400 mL anhydrous ethyl acetate was dropwise added. After the dropwiseaddition, the reaction was continued for 1 h and generate a crudeproduct, which was centrifuged and purified for several times to affordthe antibacterial compound having a terminal isocyanate.

In addition to 3,3′-iminobis(N,N-dimethyl propylamine), amines forpreparation in this example may also be other tertiary amine or pyridinehaving an active hydrogen atom, such as but not limited to N,N-dimethylethanolamine, N,N-dimethyl ethylenediamine, N,N-diethyl ethanolamine,N,N-diisopropyl ethanolamine, N,N-di-n-butyl ethanolamine,N,N-di-n-pentyl ethanolamine, N,N-dicyclohexyl ethanolamine,4-hydroxymethylpiperidine or 2,6-dimethyl-4-aminopyridine.

Example 8

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml dibutyl tin dilaurate, 21.8 g (0.16 mol)4-hydroxymethylpiperidine was slowly dropwise added thereto, using adropping funnel under stirring at the temperature of 30° C. After thedropwise addition, the reaction was continued for 1 h, and the stirringwas continued for 12 h at this temperature. Then, 24.4 g (0.2 mol)propane sultone dissolved in 400 mL anhydrous THF was dropwise added.After the dropwise addition, the reaction was continued for 1 h andgenerate a crude product, which was centrifuged and purified for severaltimes to afford the antibacterial compound having a terminal isocyanate.

The nitrogen-containing compound for preparation in this exampleincludes a functional group having an active hydrogen atom such as ahydroxyl, an amino or a thiol, and may be pyridine compounds or tertiaryamines, which may be substituted or unsubstituted aliphatic, alicyclicor aromatic. In addition to 4-hydroxymethylpiperidine, thenitrogen-containing compound may also be 2,6-dimethyl-4-aminopyridine,N,N-dimethyl ethanolamine, N,N-dimethyl ethylenediamine, N,N-diethylethanolamine, N,N-diisopropyl ethanolamine, N,N-di-n-butyl ethanolamine,N,N-di-n-pentyl ethanolamine, N,N-dicyclohexyl ethanolamine,3,3′-iminobis(N,N-dimethyl propylamine), 4-methylpyridine, or2,6-dimethyl-4-aminopyridine, etc. The above is merely examples of anoptional amine/pyridine compound and is not intended to limit the scopeof the nitrogen-containing compound in this reaction, and any pyridineor tertiary amine compound having an active hydrogen atom may be used asa reactant, for example, 4-hydroxypyridine.

Example 9

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml stannous octanoate, 24.4 g (0.2 mol) 2,6-dimethyl-4-aminopyridinewas slowly dropwise added thereto, using a dropping funnel understirring at the temperature of 30° C. After the dropwise addition, thereaction was continued for 1 h, and the stirring was continued for 12 hat this temperature. Then, 24.4 g (0.2 mol) propane sultone dissolved in400 mL anhydrous THF was dropwise added. After the dropwise addition,the reaction was continued for 1 h and generate a crude product, whichwas centrifuged and purified for several times to afford theantibacterial compound having a terminal isocyanate.

Although stannous octanoate was used as a catalyst in this example, acatalyst is not always necessary and an organic amine compound havinghigher activity can react directly with a compound having a plurality ofisocyanates in the absence of the catalyst. In a preparation using acatalyst, materials used as a catalyst may be described according toExample 1.

The nitrogen-containing compound used in this example for preparation,includes a group having an active hydrogen atom such as an amino, ahydroxyl, or a thiol, in addition to pyridine nitrogen atoms or tertiaryamine nitrogen atoms in the structure thereof. As an example, inaddition to 2,6-dimethyl-4-aminopyridine, the nitrogen-containingcompound may also be N,N-dimethyl ethanolamine, N,N-dimethylethylenediamine, N,N-diethyl ethanolamine, N,N-diisopropyl ethanolamine,N,N-di-n-butyl ethanolamine, N,N-di-n-pentyl ethanolamine,N,N-dicyclohexyl ethanolamine, 3,3′-iminobis(N,N-dimethyl propylamine),4-hydroxymethylpiperidine, 4-thiomethylpyridine, 2-dimethylaminoethanethiol, 2-diethylamino ethanethiol, 2-dimethylamino propanethiol,2-diethylamino propanethiol, 2,6-diethyl-4-aminopyridine, or4-aminopyridine whose 2-position or 6-position is substituted by otheralkyl, halogen (—F, —Cl, —Br, —I), NO₂ or an alkoxyl, etc.

Example 10

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml dibutyl tin dilaurate, 17.8 g (0.2 mol) dimethyl ethanolamine(HOCH₂CH₂N(CH₃)₂) was slowly dropwise added thereto, using a droppingfunnel under stirring at the temperature of 30° C. After the dropwiseaddition, the reaction was continued for 1 h, and the stirring wascontinued for 12 h at this temperature. Then, 42.2 g (0.2 mol) sodium2-bromoethanesulfonate dissolved in 400 mL anhydrous THF was dropwiseadded. After the dropwise addition, the reaction was continued for 1 hand generate a crude product, which was centrifuged and purified forseveral times to afford the antibacterial compound having a terminalisocyanate.

In the reaction, the function of sodium 2-bromoethanesulfonate is toremove the bromine atom by receiving a nucleophilic attack from the Natom and thus to form a quaternary ammonium group, forming a finalzwitterionic compound. Similarly, sodium sulfonate substituted by otherhalogen or other easily leaving groups, such as sodium2-chloroethanesulfonate, sodium 2-iodoethanesulfonate, sodium2-chloropropanesulfonate, sodium 2-bromopropanesulfonate, sodium2-iodopropanesulfonate, or sodium 2-p-(phenylsulfonyl)propanesulfonate,may also be used in the second step of the reaction, since a similarreaction may take place.

The addition of the sodium 2-bromoethanesulfonate solution may bemanually dropping or dropping using a mechanical drip machine, and thedropping speed may be constant or may be continuously changed as thereaction progresses.

Example 11

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml dibutyl tin dilaurate, 17.8 g (0.2 mol) dimethyl ethanolamine(HOCH₂CH₂N(CH₃)₂) was slowly dropwise added thereto, using a droppingfunnel under stirring at the temperature of 30° C. After the dropwiseaddition, the reaction was continued for 1 h, and the stirring wascontinued for 12 h at this temperature. Then, 37.4 g (0.22 mol) sodium4-bromobutyrate dissolved in 400 mL anhydrous THF was dropwise added.After the dropwise addition, the reaction was continued for 1 h andgenerate a crude product, which was centrifuged and purified for severaltimes to afford the antibacterial compound having a terminal isocyanate.

In the reaction, the function of sodium 4-bromobutyrate is to remove thebromine atom by receiving a nucleophilic attack from the N atom and thusto form a quaternary ammonium group. Similarly, metal carboxylatesubstituted by other halogen or other leaving groups. The halogen mayinclude but not limited to chlorine, bromine, and iodine; other leavinggroups may include but not limited to p-tosyl (—OTs), mesyl (—OMs), ortrifluoromesyl (—OTf); the metal in metal carboxylate may include butnot limited to lithium, sodium, potassium, ammonium, silver, magnesium,or calcium; carboxylic acid may include but not limited to acetic acid,propionic acid, butyric acid, valeric acid, or carboxylic acid havingmore carbon atoms; the position of halogen or other substituents may beα, β, γ positions approaching to the carbon atom in the carboxyl.Typical halogen substituted metal carboxylate may include but notlimited to sodium chloroacetate, sodium bromoacetate, sodiumiodoacetate, sodium 2-chloropropionate, sodium 3-chloropropionate,sodium 2-bromopropionate, sodium 3-bromopropionate, sodium2-iodopropionate, sodium 3-iodopropionate, sodium 4-chlorobutyrate, orsodium 4-iodobutyrate. The above materials may also be used in thesecond step of the reaction, since they can similarly react withtertiary amines.

The addition of the sodium 4-bromobutyrate solution may be manuallydropping or dropping using a mechanical drip machine, and the droppingspeed may be constant or may be continuously changed as the reactionprogresses.

As for separation of the final product, different separation methods maybe used according to different forms of the final product; if the finalproduct is an oil or sticky solid, the final product can be purified byextraction or distillation; if the final product is a precipitate, thefinal product can be purified by centrifugation or filtration or thelike.

Example 12

9.3 g (0.2 mol) ethanol and 20.2 g (0.2 mol) triethylamine (TEA) wereweighted and dissolved in 100 ml anhydrous THF. The mixture was added toa round flask with mechanical stirring, and was cooled at −20° C. for 20min and maintained at −20° C. To the reaction vessel, 28.392 g (0.2 mol)2-chloro-oxy-1,3,2-dioxaphospholane (COP) dissolved in 30 ml anhydrousTHF was dropwise added. After the dropwise addition, the mixture wasallowed to stand at −20° C. until a precipitate is generated. Theprecipitate was distilled under vacuum to give2-ethoxy-2-oxy-1,3,2-dioxaphospholane (EOP).

44.6 g (0.2 mol) isophorone diisocyanate (IPDI) was weighted and addedto a round flask with mechanical stirring. After adding a catalyst of0.2 ml dibutyl tin dilaurate, 17.8 g (0.2 mol) dimethyl ethanolamine(HOCH₂CH₂N(CH₃)₂) was slowly dropwise added thereto, using a droppingfunnel under stirring at the temperature of 30° C. After the dropwiseaddition, the reaction was continued for 1 h, and the stirring wascontinued for 12 h at this temperature. Then, 30.4 g (0.2 mol) EOPdissolved in 400 mL anhydrous THF was dropwise added at 75° C. After thedropwise addition, the reaction was continued for 24 h and generate acrude product, which was centrifuged and purified for several times toafford the antibacterial compound having a terminal isocyanate.

In the above reaction, ethanol attacked the P atom of COP, and HCl waslost, so that a substitution reaction has taken place to give theproduct EOP. Similarly, in addition to ethanol, those can react with COPin a substitution reaction may also be other fatty alcohols, alicyclicalcohols or aromatic alcohols, such as methanol, n-propanol,isopropanol, n-butanol, n-pentanol, n-heptanol, vinyl alcohol, propenol,cyclopropanol, cyclopentanol, cyclohexanol, or benzyl alcohol.

Although COP was used as a phosphorus-containing reagent in thisexample, the phosphorus-containing reagent may be other2-halo-1,3,2-dioxaphosphorus heterocyclic compounds in which the numberof atoms in the ring may be 4, 5, 6, 7, 8 or 9, preferably 5, 6, or 7,i.e., 2-halo-1,3,2-dioxaphospholane, 2-halo-1,3,2-dioxaphosphinan or2-halo-1,3,2-dioxaphosphepine. In this reaction, the phosphorus atom in2-halo-1,3,2-dioxaphosphorus heterocyclic compound may be bound to ahalogen atom in addition to binding to the oxygen atom. As disclosed inU.S. Pat. No. 2,982,862, the halogen atom in this compound may includechlorine, bromine, or iodine which is easily substituted by the alkoxylin alcohols due to a better leaving property. The hydrogen atom bound tothe carbon atom in the ring may be substituted by one or more alkyls,such as methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, ort-butyl.

In addition to COP, the compound may also include but not limited to2-chloro-4,5-dimethyl-1,3,2-dioxaphospholane-2-oxide,2-chloro-1,3,2-dioxaphosphinan-2-oxide,2-chloro-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphinan-2-oxide,2-chloro-4,6-dimethyl-1,3,2-dioxaphosphinan-2-oxide,2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan-2-oxide,2-chloro-1,3,2-dioxaphosphepine-2-oxide,2-chloro-1,3,2-dioxaphosphocane-2-oxide,2-bromo-1,3,2-dioxaphospholane-2-oxide,2-bromo-1,3,2-dioxaphosphinan-2-oxide, or2-bromo-5,5-dimethyl-1,3,2-dioxaphosphinan-2-oxide.

Although triethylamine was used as a reaction auxiliary in this example,other tertiary amines which do not contain active hydrogen may also beused, such as trimethylamine, tri-n-propylamine, tri-iso-propylamine,tri-n-butylamine, N-methyl dioctylamine, N,N-dimethyl cyclopentylamineor N,N-dimethyl cyclohexane. In this alcoholysis reaction, tertiaryamine was used as alkali to assist in removing HCl.

Although THF was used as an organic solvent, the organic solvent mayalso be acetonitrile, DMF, DMSO, anhydrous butanone, anhydrous acetone,cyclohexanone, toluene, ethyl acetate, n-propyl acetate, n-butylacetate, acetonitrile, 1,4-dioxan ring, N-methylpyrrolidone, pyridin,N,N-dimethylformamide, or a mixture of two or more solvents above.

In the second step of the reaction, the function of EOP is to make aring-opening reaction occur by the C atom bound to the O atom in thering receiving a nucleophilic attack from the N atom and thus to form aquaternary ammonium group.

The addition of the EOP solution may be manually dropping or droppingusing a mechanical drip machine, and the dropping speed may be constantor may be continuously changed as the reaction progresses.

As for separation of the final product, different separation methods maybe used according to different forms of the final product; if the finalproduct is an oil, the final product can be purified by extraction ordistillation; if the final product is a precipitate, the final productcan be purified by centrifugation or filtration or the like.

Example 13

9.3 g (0.2 mol) ethanol and 20.2 g (0.2 mol) triethylamine (TEA) wereweighted and dissolved in 100 ml anhydrous THF. The mixture was added toa round flask with mechanical stirring, and was cooled at −20° C. for 20min and maintained at −20° C. To the reaction vessel, 28.392 g (0.2 mol)2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan-2-oxide dissolved in 30 mlanhydrous THF was dropwise added. After the dropwise addition, themixture was allowed to stand at −20° C. until a precipitate isgenerated. The precipitate was distilled under vacuum and purified togive 2-ethoxy-2-oxy-1,3,2-dioxaphosphinan.

50.1 g (0.2 mol) diphenylmethane diisocyanate (MDI) was added to a roundflask with mechanical stirring. After adding a catalyst of 0.2 mldibutyl tin dilaurate, 23.5 g (0.2 mol) N,N-diethyl ethanolamine(HOCH₂CH₂N(CH₂CH₃)₂) was slowly dropwise added thereto, using a droppingfunnel under stirring at the temperature of 30° C. After the dropwiseaddition, the reaction was continued for 1 h, and the stirring wascontinued for 12 h at this temperature. Then, 30.4 g (0.2 mol)2-ethoxy-2-oxy-1,3,2-dioxaphosphinan dissolved in 400 mL anhydrous THFwas dropwise added at 70° C. After the dropwise addition, the reactionwas continued for 24 h and generate a crude product, which wascentrifuged and purified for several times to afford the antibacterialcompound having a terminal isocyanate.

The antibacterial compound provided by this example of the presentdisclosure is a zwitterionic compound having a terminal isocyanate. Thepositive charge of a quaternary nitrogen atom may damage thecytomembrane of the microorganism, thereby denaturing the protein anddamaging the cell structure. The microorganism may include but notlimited to E. coli, S. typhimurium, P. aeruginosa, S. aureas, C.albicans, sulfate reducing bacteria, Gram-positive bacteria,Gram-negative bacteria, S. epidermidis, E. faecalis, C. xerosis, B.anthracis, etc. The antibacterial compound may be used as a sterilizingagent or a bacteriostatic agent to prevent infections, to killmicroorganisms or to inhibit physiological functions of themicroorganisms, and thus may effectively treat the infections caused bythese microorganisms, or control pollution caused by the same.

The antibacterial compound provided by this example of the presentdisclosure may be chemically bound to the surface of the materialthrough the terminal isocyanate. The antibacterial compound may beapplied to textile, medicine, food, and agriculture fields, but notlimited thereto. For example, the isocyanate may be bound to a hydroxylor amino on the surface of a fiber, a cotton textile, or a nylon toproduce a antibacterial textile with detergent resistance; may be boundto a hydroxyl or amino on the surface of a medical perfusion tube orpackaging material to produce an antibacterial medical product; or maybe bound to a hydroxyl or amino on the surface of a food package or foodpreservation material to produce an antibacterial packaging material.

The products according to Examples 1-13 of the present disclosure weretested for minimum inhibitory concentration of E. coli (American TypeCulture Collection ATCC 25922) and S. aureas (ATCC 6538). The minimuminhibitory concentration (MIC) is the lowest concentration ofantibacterial agents that can inhibit the visible growth of bacteriaafter 24 h culture in a specific environment. Methods for determiningthe minimum inhibitory concentration can be a constant broth dilutionmethod, a trace broth dilution method, an agar dilution method or an Eexperiment. The antibacterial concentration test results of theantibacterial agents of Examples 1-13 of the present disclosure areshown in Table 1.

TABLE 1 Minimum inhibitory concentrations (MIC, unit: μmol/mL) ofantibacterial agents in Examples 1-13 Strain Sample No. E. coli S.aureas Example 1 16 13 Example 2 12 10 Example 3 11 8 Example 4 12 10Example 5 10 7 Example 6 12 10 Example 7 7 3 Example 8 10 7 Example 9 108 Example 10 12 9 Example 11 10 8 Example 12 9 8 Example 13 9 8

The compounds obtained in examples of the present disclosure have aquite low inhibitory concentration for the bacteria, which is sufficientto ensure that the number of bacterial populations is extremely low anddo little harm to human health, when using the compounds.

Treating the clean glass surface with the products obtained in Examples1-13 and the antibacterial activity and the durable antibacterialactivity were tested using a colony counting method. The bacteria usedin this implementation were E. coli and S. aureas, and the results areshown in Table 2.

TABLE 2 Durable antibacterial activity analysis for glass surfacesmodified by antibacterial agents (plate counting method) Wash numberSample Strain 0 10 50 100 Example 1 E. coli 99.99% 99.8% 97.5% 96.0% S.aureas 99.99% 99.9% 98.6% 96.5% Example 2 E. coli 99.99% 99.9% 97.3%95.9% S. aureas 99.99% 99.9% 98.9% 96.6% Example 3 E. coli 99.99% 99.8%98.5% 96.5% S. aureas 99.99% 99.9% 99.0% 97.2% Example 4 E. coli 99.99%99.8% 98.0% 94.2% S. aureas 99.99% 99.9% 98.6% 95.9% Example 5 E. coli99.99% 99.7% 99.0% 96.5% S. aureas 99.99% 99.9% 99.5% 98.5% Example 6 E.coli 99.99% 99.8% 97.3% 97.9% S. aureas 99.99% 99.9% 98.5% 94.2% Example7 E. coli 99.99% 99.92% 99.9% 95.2% S. aureas 99.99% 99.95% 99.9% 95.2%Example 8 E. coli 99.99% 99.7% 97.3% 94.7% S. aureas 99.99% 99.9% 98.5%95.8% Example 9 E. coli 99.99% 99.8% 97.1% 94.3% S. aureas 99.99% 99.9%98.5% 95.2% Example 10 E. coli 99.99% 99.8% 97.5% 94.1% S. aureas 99.99%99.9% 98.9% 95.3% Example 11 E. coli 99.99% 99.8% 97.1% 94.5% S. aureas99.99% 99.9% 98.3% 95.8% Example 12 E. coli 99.99% 99.8% 97.6% 95.2% S.aureas 99.99% 99.9% 98.7% 96.2% Example 13 E. coli 99.99% 99.8% 97.5%95.3% S. aureas 99.99% 99.9% 98.8% 96.5%

According to the above table, the antibacterial compounds provided bythe examples of the present disclosure have excellent antibacterialproperties and durability against common bacteria such as E. coli and S.aureas. Even after repeated washing, the antibacterial properties onlyslightly reduced, but still remained at 94% or more.

The antibacterial compounds provided by the examples of the presentdisclosure have a reactive functional group—an isocyanate, which maychemically bond to the functional group present on the surfaces of avariety of materials, such as a hydroxyl in cotton fibers, fibrilia,polyester fibers (e.g., dacron PET), or poly lactic acid (PLA), an aminoin nylon, as well as an amide in wool, pashm, silk, chinlon, or aramid,and anchor antibacterial components on the surfaces of materials, thusimparting durable soil resistance to the materials or product surfacestreated by the reactive antibacterial compounds. Meanwhile, thepreparation method of the compound is simple, the condition is easy tocontrol, and the compound is easy to be industrialized, which facilitatea wide use range of the compound. The antibacterial compounds providedby the examples of the present disclosure have broad industrialapplication prospects.

The foregoing is a further detailed description of embodiments of thepresent disclosure in conjunction with examples, which facilates thoseskilled in the art to readily understand and apply the antibacterialcompounds provided by the embodiments of the present disclosure, and theembodiments of the present disclosure are not limiting. It should benoted that, without departing from the spirit of the embodiments of thepresent disclosure, other modifications or improvements may occur andare intended to those skilled in the art, and are within the scope ofthe present disclosure defined by the claims.

We claim:
 1. An antibacterial compound represented by formula (II):

wherein: G₁ represents OCN-M-NHCOOG′, OCN-M-NHCONHG′, OCN-M-NHCOSG′,OCN-M-COOG′, or OCN-M-COONHG′; M represents a divalent unsubstituted orsubstituted alkyl, cycloalkyl, or aryl having from 1 to 18 carbon atoms;G′ represents a divalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 18 carbon atoms; G₂ and G₃ independently foreach occurrence represent —H, —F, —Cl, —Br, —I, —OCH₃, —OCH₂CH₃, —OPr,—CN, —SCN, —NO, —NO₂, a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 7 carbon atoms; G₄ represents adivalent unsubstituted or substituted alkyl, cycloalkyl, or aryl havingfrom 1 to 18 carbon atoms; X represents —COO, —SO₃, or —OPO₂OR₅; and R₅represents a monovalent unsubstituted or substituted alkyl, cycloalkyl,or aryl having from 1 to 6 carbon atoms.
 2. The antibacterial compoundof claim 1, wherein the G₁ represents OCN-M-NHCOOG′ or OCN-M-NHCONHG′.3. The antibacterial compound of claim 1, wherein the G₂ and G₃independently for each occurrence represent —H, —CH₃, —CH₂CH₃, —NO₂, —F,—Cl, —Br, or —I.
 4. The antibacterial compound of claim 1, wherein theG₄ and the G′ independently for each occurrence represent —(CH₂)_(n)—,and n is an integer within a range from 1 to
 18. 5. The antibacterialcompound of claim 1, wherein the M represents:


6. A preparation method for an antibacterial compound according to claim1, comprising: 1) reacting pyridine represented by general formula (V)with a reactant B represented by general formula (IV), and generating amixture;

wherein: the Q represents —OH, —NH₂, or —SH; G′ represents a divalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to18 carbon atoms; G₂ and G₃ independently for each occurrence represent—H, —F, —Cl, —Br, —I, —OCH₃, —OCH₂CH₃, —OPr, —CN, —SCN, —NO, —NO₂, amonovalent unsubstituted or substituted alkyl, cycloalkyl, or arylhaving from 1 to 7 carbon atoms; D represents —COOH or —NCO; and Lrepresents a divalent unsubstituted or substituted alkyl, cycloalkyl, oraryl having from 1 to 18 carbon atoms; 2) reacting the mixture with areactant A, and generating the antibacterial compound represented byformula (II); wherein: the reactant A represents propane sultone, butanesultone, β-propiolactone, X(CH₂)_(v)CO₂—Mt⁺, X(CH₂)vSO₃-Mt⁺, or cyclicphosphate ester, the X represents Br, Cl, or I, v is an integer greaterthan 0, Mt⁺ represents Li⁺, Na⁺, K⁺, NH₄ ⁺, Ag⁺, ½Mg²⁺, or ½Ca²⁺, andthe cyclic phosphate ester represents:

wherein: R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms; and R₆ represents adivalent unsubstituted or substituted alkyl having from 1 to 6 carbonatoms.
 7. The preparation method for the antibacterial compound of claim6, wherein the pyridine and the reactant B are reacting in the presenceof catalyst C, and the catalyst C represents at least one of organicamine, a phosphorus compound, or a metal-containing catalyst.
 8. Thepreparation method for the antibacterial compound of claim 7, whereinthe metal-containing catalyst represents tin tetrachloride, tetrabutyltin, tributyl tin chloride, dibutyl tin dichloride, butyl tintrichloride, tributyl tin cyanide, dibutyl tin diacetate, dibutyl tindioctoate, tributyl tin octoate, diphenyl tin dioctoate, dibutyl tindibutoxy, dibutyl tin bis(acetylacetoate), dibutyl tinbis(isooctylmaleate), dioctoate tin oxide, dibutyl tin sulfide, stannousoleate, stannous tartrate, dibutyl tin dilaurate, stannous octoate, ormetal naphthenate.
 9. The preparation method for the antibacterialcompound of claim 8, wherein the catalyst C represents the metalnaphthenate.
 10. The preparation method for the antibacterial compoundof claim 9, wherein the metal naphthenate represents at least one ofcopper naphthenate, zinc naphthenate, lead naphthenate, lithiumnaphthenate, cobalt naphthenate, nickel naphthenate, cadmiumnaphthenate, mercury naphthenate, indium naphthenate, or bismuthnaphthenate.
 11. An antibacterial compound represented by formula (II):

wherein: G₁ represents OCN-M-NHCOOG′ or OCN-M-NHCONHG′; M represents adivalent unsubstituted or substituted alkyl, cycloalkyl, or aryl havingfrom 1 to 18 carbon atoms; G′ represents a divalent unsubstituted orsubstituted alkyl, cycloalkyl, or aryl having from 1 to 18 carbon atoms;G₂ and G₃ independently for each occurrence represent —H, —CH₃, —CH₂CH₃,—NO₂, —F, —Cl, —Br, or —I; G₄ represents a divalent unsubstituted orsubstituted alkyl, cycloalkyl, or aryl having from 1 to 18 carbon atoms;X represents —COO, —SO₃, or —OPO₂OR₅; and R₅ represents a monovalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to6 carbon atoms.
 12. The antibacterial compound of claim 11, wherein theG₄ and the G′ independently for each occurrence represent —(CH₂)_(n)—,and n is an integer within a range from 1 to
 18. 13. The antibacterialcompound of claim 11, wherein the M represents:


14. A preparation method for an antibacterial compound according toclaim 11, comprising: 1) reacting pyridine represented by generalformula (V) with a reactant B represented by general formula (IV), andgenerating a mixture;

wherein: the Q represents —OH, —NH₂, or —SH; G′ represents a divalentunsubstituted or substituted alkyl, cycloalkyl, or aryl having from 1 to18 carbon atoms; G₂ and G₃ independently for each occurrencerepresent—represent —H, —CH₃, —CH₂CH₃, —NO₂, —F, —Cl, —Br, or —I; Drepresents —COOH or —NCO; and L represents a divalent unsubstituted orsubstituted alkyl, cycloalkyl, or aryl having from 1 to 18 carbon atoms;2) reacting the mixture with a reactant A, and generating theantibacterial compound represented by the formula (II); wherein: thereactant A represents propane sultone, butane sultone, β-propiolactone,X(CH₂)_(v)CO₂—Mt⁺, X(CH₂)vSO₃-Mt⁺, or cyclic phosphate ester, the Xrepresents Br, Cl, or I, v is an integer greater than 0, Mt⁺ representsLi⁺, Na⁺, K⁺, NH₄ ⁺, Ag⁺, ½Mg²⁺, or ½Ca²⁺, and the cyclic phosphateester represents:

wherein: R₅ represents a monovalent unsubstituted or substituted alkyl,cycloalkyl, or aryl having from 1 to 6 carbon atoms; and R₆ represents adivalent unsubstituted or substituted alkyl having from 1 to 6 carbonatoms.
 15. The preparation method for the antibacterial compound ofclaim 14, wherein the pyridine and the reactant B are reacting in thepresence of catalyst C, and the catalyst C represents at least one oforganic amine, a phosphorus compound, or a metal-containing catalyst.16. The preparation method for the antibacterial compound of claim 15,wherein the metal-containing catalyst represents tin tetrachloride,tetrabutyl tin, tributyl tin chloride, dibutyl tin dichloride, butyl tintrichloride, tributyl tin cyanide, dibutyl tin diacetate, dibutyl tindioctoate, tributyl tin octoate, diphenyl tin dioctoate, dibutyl tindibutoxy, dibutyl tin bis(acetylacetoate), dibutyl tinbis(isooctylmaleate), dioctoate tin oxide, dibutyl tin sulfide, stannousoleate, stannous tartrate, dibutyl tin dilaurate, stannous octoate, ormetal naphthenate.
 17. The preparation method for the antibacterialcompound of claim 16, wherein the catalyst C represents the metalnaphthenate.
 18. The preparation method for the antibacterial compoundof claim 17, wherein the metal naphthenate represents at least one ofcopper naphthenate, zinc naphthenate, lead naphthenate, lithiumnaphthenate, cobalt naphthenate, nickel naphthenate, cadmiumnaphthenate, mercury naphthenate, indium naphthenate, or bismuthnaphthenate.
 19. An antibacterial compound selected from a groupconsists of


20. A preparation method for an antibacterial compound according toclaim 19, comprising: 1) reacting pyridine represented by generalformula (V) with a reactant B represented by general formula (IV), andgenerating a mixture;

wherein: the Q represents —OH, or —NH₂; G′ represents a bond ormethylene; G₂ and G₃ independently for each occurrence represent —H or—CH; D represents —NCO; and L represents a substituted cycloalkyl havingfrom 1 to 18 carbon atoms; 2) reacting the mixture with a propanesultone, and generating the antibacterial compound; wherein the pyridineand the reactant B are reacting in the presence of catalyst C, and thecatalyst C represents at least one of organic amine and ametal-containing catalyst, and wherein the metal-containing catalystrepresents dibutyl tin dilaurate or stannous octoate.